Can biowarfare agents be defeated with light? The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Vatansever, Fatma, Cleber Ferraresi, Marcelo Victor Pires de Sousa, Rui Yin, Ardeshir Rineh, Sulbha K Sharma, and Michael R Hamblin. 2013. “Can biowarfare agents be defeated with light?” Virulence 4 (8): 796-825. doi:10.4161/viru.26475. http://dx.doi.org/10.4161/ viru.26475. Published Version doi:10.4161/viru.26475 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879868 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA SPECIAL FOCUS REVIEW Virulence 4:8, 796–825; November 15, 2013; © 2013 Landes Bioscience Can biowarfare agents be defeated with light? Fatma Vatansever1,2, Cleber Ferraresi1,3,4,5, Marcelo Victor Pires de Sousa1,6, Rui Yin1,2,7, Ardeshir Rineh1,8, Sulbha K Sharma1,9, and Michael R Hamblin1,2,10,* 1Wellman Center for Photomedicine; Massachusetts General Hospital; Boston MA USA; 2Harvard Medical School; Department of Dermatology; Boston, MA USA; 3Laboratory of Electro-thermo-phototherapy; Department of Physical Therapy; Federal University of São Carlos; São Paulo, Brazil; 4Post-Graduation Program in Biotechnology; Federal University of São Carlos; São Paulo, Brazil; 5Optics Group; Physics Institute of Sao Carlos; University of São Paulo; São Carlos, Brazil; 6Laboratory of Radiation Dosimetry and Medical Physics; Institute of Physics, São Paulo University, São Paulo, Brazil; 7Department of Dermatology; Southwest Hospital; Third Military Medical University; Chongqing, PR China; 8School of Chemistry; University of Wollongong; Wollongong, NSW Australia; 9Raja Ramanna Centre for Advanced Technology; Indore, India; 10Harvard-MIT Division of Health Sciences and Technology; Cambridge, MA USA Keywords: biowarfare, bioterrorism, photocatalysis, photocatalytic inactivation, microbial cells, ultraviolet light, germicidal ultraviolet, photo inactivation, UV dosimeters, titanium dioxide, psorales, photodynamic therapy, blue light inactivation Introduction: Biological Warfare Biological warfare and bioterrorism is an unpleasant fact of 21st century life. Highly infectious and profoundly virulent and Bioterrorism Agents diseases may be caused in combat personnel or in civilian In recent years, the possibility of biological warfare and bio- populations by the appropriate dissemination of viruses, bac- teria, spores, fungi, or toxins. Dissemination may be airborne, terrorism has become of increasing concern to both military waterborne, or by contamination of food or surfaces. Coun- planners and civil defense authorities. The mailing of anthrax termeasures may be directed toward destroying or neutral- spore containing letters to destinations within the United States izing the agents outside the body before infection has taken in 2001 brought the sudden realization that bioterrorism is not place, by destroying the agents once they have entered the merely a theoretical threat but a real and present danger. Since body before the disease has fully developed, or by immuniz- then, much thought and planning has gone into defining possible ing susceptible populations against the effects. A range of biowarfare and bioterrorism agents. There are six requirements light-based technologies may have a role to play in biodefense for these agents that are relevant here: countermeasures. Germicidal UV (UVC) is exceptionally active 1) A high degree of morbidity and lethality. in destroying a wide range of viruses and microbial cells, and 2) Highly infectious microbes or highly toxic substances. recent data suggests that UVC has high selectivity over host 3) Easy to distribute widely in an active form. mammalian cells and tissues. Two UVA mediated approaches may also have roles to play; one where UVA is combined with 4) Easy to produce in bulk and store until delivered. titanium dioxide nanoparticles in a process called photoca- 5) Reasonably hardy in the environment after distribution. talysis, and a second where UVA is combined with psoralens 6) Bacteria should be genetically engineered to be resistant to (PUVA) to produce “killed but metabolically active” microbial known antibiotic drugs. cells that may be particularly suitable for vaccines. Many micro- The 2001 bioterrorist attacks in the US using anthrax spores bial cells are surprisingly sensitive to blue light alone, and blue and the US Postal Service as the spreading medium have once light can effectively destroy bacteria, fungi, and Bacillus spores more emphasized the need of early detection and decontami- and can treat wound infections. The combination of photosen- nation of critical facilities in the shortest possible time. During sitizing dyes such as porphyrins or phenothiaziniums and red the recent decade there has been a remarkable progress in the light is called photodynamic therapy (PDT) or photoinactiva- detection, protection, and decontamination of biological war- tion, and this approach cannot only kill bacteria, spores, and fare agents since various and sophisticated detection/decon- fungi, but also inactivate viruses and toxins. Many reports have highlighted the ability of PDT to treat infections and stimulate tamination methods have been developed and implemented. the host immune system. Finally pulsed (femtosecond) high Nevertheless the threat of biological warfare agents and their power lasers have been used to inactivate pathogens with possible use in bioterrorist attacks still remains a leading cause some degree of selectivity. We have pointed to some of the of concern in the global community. Furthermore, in the past ways light-based technology may be used to defeat biological decade there have been threats to the global society due to the warfare in the future. emergence of new infectious diseases and/or re-emergence of old infectious diseases that were considered eliminated. Adding to the milieu the observed global rise in the antimicrobial resis- tance, the preparedness of societies against these agents becomes obvious. Under these circumstances it becomes obvious that the field requires better knowledge about the disease agents, more *Correspondence to: Michael R Hamblin; Email: research, better training and diagnostic facilities, and improved [email protected] public health system1 (see Table 1). Submitted: 06/03/2013; Revised: 09/10/2013; Accepted: 09/12/2013 The emergence of bacterial strains that are resistant to all http://dx.doi.org/10.4161/viru.26475 known antibiotics represents a major challenge to human health. 796 Virulence Volume 4 Issue 8 www.landesbioscience.com Table 1. Common biological warfare agent characteristics SPECIA L Organism Person to Infective dose FOCU Disease Etiologic agent Symptoms Incubation period Mortality Treatment persistence person? (aerosol) S RE V Bacterial agents IEW Spores of Bacillus anthracis Fever, malaise, fatigue, Spores can be Anthrax (encapsulated gram- cough, mild chest High once symptoms Ciprofloxacin or viable for >40 No 8000–50 000 spores 1–6 d (inhalation) positive bacillus); reservoir: discomfort, respiratory appear doxycyline years the soil distress, shock Irregular fever, Genus Brucella 6 wks in dust and headache, malaise, Doxycycline + Brucellosis (B. melitensis, B. abortus, 10 wks in soil or chills, sweating, No 10–100 organisms 5–60 d 5% untreated rifampin B. suis, B. canis) water myalgia, joint pain, depression High fever, chills, Up to 1 year in Pneumonic Yersinia pestis; reservoir: headache, productive High unless treated Gentamycin or soil, 270 d in live Yes, highly <100 organisms 2–3 d plague rodents cough-watery then in 12–24 h doxycycline tissue bloody Withstands heat Fever, chills, headache, Virulence and drying; Coxiella burnetii; reservoir: diaphoresis, malaise, Tetracycline or Q fever persists in Rarely 1–10 organisms 2–14 d Very low animals fatigue, anorexia, doxycycline environment for weight loss weeks to months Months in moist Fever, headache, Ciprofloxacin, Francisella tularensis; Moderate if Tularemia soil or other malaise, weight loss, No 10–50 organisms 1–21 d doxycycline, or reservoir: rabbits, rodents untreated media nonproductive cough gentamycin Fever, rigors, sweating, myalgia, headache, Amoxicillin, B. mallei; reservoir horses, pleuritis, chest pain, Glanders Stable Yes ? 10–14 d Varies tetracycline, or mules, donkeys splenomegaly, trimethoprim/sulfa generalized popular/ pustular eruptions Fever, aching chest pain, cough-productive and nonproductive, Amoxicillin, Burkholderia pseudomallei; severe dyspnea, Moderate if tetracycline, Melioidosis Stable No ? 10–14 d reservoir: soil and water diarrhea, flushing of untreated trimethoprim/sulfa, the skin, cyanosis, rash ceftazidime SPECIA that can progress to pustular exanthem L FOCU aLD, lethal dose μg/kg; bMay be effective; cRicin and botulinum toxin are lethal at all levels. The mortality levels terminology is as defined by the Centers for Disease Control. Compiled and modified from reference 246. S RE V IEW 797 798 Table 1. Common biological warfare agent characteristics (continued) Organism Person to Infective dose Disease Etiologic agent Symptoms Incubation period Mortality Treatment persistence person? (aerosol) Viral agents Fever, rigors, severe headache, backache, malaise, vomiting, Variola, poxvirus family; delirium, acute